Ras and Rab Interactor 3: From Cellular Mechanisms to Human Diseases

Abstract

Ras and Rab interactor 3 (RIN3) functions as a Guanine nucleotide Exchange Factor (GEF) for some members of the Rab family of small GTPase. By promoting the activation of Rab5, RIN3 plays an important role in regulating endocytosis and endocytic trafficking. In addition, RIN3 activates Ras, another small GTPase, that controls multiple signaling pathways to regulate cellular function. Increasing evidence suggests that dysregulation of RIN3 activity may contribute to the pathogenesis of several disease conditions ranging from Paget's Disease of the Bone (PDB), Alzheimer's Disease (AD), Chronic Obstructive Pulmonary Disease (COPD) and to obesity. Recent genome-wide association studies (GWAS) identified variants in the RIN3 gene to be linked with these disease conditions. Interestingly, some variants appear to be missense mutations in the functional domains of the RIN3 protein while most variants are located in the noncoding regions of the RIN3 gene, potentially altering its gene expression. However, neither the protein structure of RIN3 nor its exact function(s) (except for its GEF activity) has been fully defined. Furthermore, how the polymorphisms/variants contribute to disease pathogenesis remain to be understood. Herein, we examine, and review published studies in an attempt to provide a better understanding of the physiological function of RIN3; More importantly, we construct a framework linking the polymorphisms/variants of RIN3 to altered cell signaling and endocytic traffic, and to potential disease mechanism(s).

Keywords: Alzheimer’s disease; RIN3; Rab5; endocytosis; trafficking.

FIGURE 1

Structure of the RIN protein family. Domain structures of individual RIN proteins. Functional domains with indicated residues are presented by frames. SH2, src homology 2; PRD: proline-rich domain; RH: Rin homology; VPS9: vacuolar protein sorting-associated protein 9; RA: Ras-association. The amino acid residues for each of these domains are marked.

FIGURE 2

Expression profile of RIN family in normal human tissues. (A): RNA levels of individual RIN genes. Data comes from HPA RNA-seq normal tissues project (Fagerberg et al., 2014). (B): Protein expression level of RIN1/2/3. Data comes from the Human Protein Atlas (https://www.proteinatlas.org/).

FIGURE 3

Potential signaling mechanism(s) regulating RIN3 GEF activity. (A): Upon activation of receptor tyrosine kinase (RTK) or tyrosine kinase (TK), while the Ras/MAP kinase signaling cascade is activated, RIN3 also via its SH2 domain binds to the phosphor-tyrosine residue (pY) leading to suppression of the GEF activity of RIN3 and Rab5 stays as GDP bound. (B): Deactivation of RTK/TK by the phosphotyrosine phosphatase (PPtase) results in attenuation of the Ras/MAP kinase signaling. Concomitantly, RIN3 is decoupled and breaks free from RTK/TK, which in turn activates the GEF activity to promote the conversion of Rab5 from GDP- to GTP-bound form.

FIGURE 4

Disease-associated variants/mutations and predicted structure of human RIN3. (A). A linear presentation of all known mutation sites in the various domains of RIN3. Missense mutations in RIN3 have been discovered thus far, all are associated with Page’s Disease of the Bone; except that: 1) W63C is linked with sporadic EOAD; 2) R279C is associated with COPD and P386S. (B). Predicted structure of human RIN3 by AlphaFold (https://alphafold.ebi.ac.uk/entry/Q8TB24). All the known mutations that have been identified are marked. For a detailed prediction of RIN3 3D structure, see supplemental movie.

FIGURE 5

A proposed model of increased RIN3 activity in disrupting axonal transport in Alzheimer’s Diseases. Neurotrophic factors (NTs) bind to and activate their respective tyrosine receptor kinases (TRKs) to form a signal complex, that is internalized into Rab5+ early endosomes for retrograde transport. Increased expression of RIN3 or the W63C variant enhances Rab5 activation, which in turn promotes APP processing to produce c-terminal fragments (CTFs)/Aβ in conjunction withCD2AP. In addition, RIN3/BIN1 increases phosphorylation of Tau. Consequently, retrograde transport of trophic signals (NT/Trk) is impaired leading to eventual neurodegeneration in AD.

FIGURE 6

Proposed mechanism by which increased RIN3 activity leads to tau phosphorylation and amyloidic processing of APP in AD.